Health-related quality of life and lifestyle changes in patients with chronic kidney disease and hyperkalaemia: Real-world data from the US, five European countries and China.

BACKGROUND: Chronic kidney disease patients have impaired health-related quality of life and an increased risk of hyperkalaemia. AIMS: The objective was to evaluate the impact of hyperkalaemia on health-related quality of life, and investigate lifestyle change recommendations, in these patients. METHODS: The Adelphi Real World Chronic Kidney Disease Specific Programme™ was used. Data were collected from physicians and patients with non-dialysis dependent stage 3a, 3b and 4 chronic kidney disease from the US, France, Germany, Spain, Italy, the UK and China. Patients completed the Kidney Disease Quality of Life Instrument and EuroQol-5D-3L. Analyses compared data between hyperkalaemic (serum potassium >5.0 mmol/L) and normokalaemic (serum potassium 3.5-5.0 mmol/L) patients. RESULTS: Overall, 1149 patients were included (hyperkalaemic: n = 216, normokalaemic: n = 933; US: n = 376, Europe: n = 490, China: n = 283). Hyperkalaemic vs normokalaemic patients experienced more symptoms (P < .001) and had numerically lower scores, indicating poorer health-related quality of life, in all Kidney Disease Quality of Life domains, with significant differences for three/five domains. Hyperkalaemic patients reported numerically lower EuroQol-5D-3L utility index and visual analogue scores, indicating poorer health status, than normokalaemic patients. A higher proportion of hyperkalaemic than normokalaemic patients were recommended to reduce dietary potassium (P < .05). More normokalaemic than hyperkalaemic patients reported making a radical change in five/six recommended lifestyle changes, with the difference significant for four/six recommendations. CONCLUSIONS: Hyperkalaemia is associated with an incremental impairment of the health-related quality of life in chronic kidney disease patients. A better understanding of the impact of hyperkalaemia in these patients could improve patient outcomes.

Associations between serum potassium and adverse clinical outcomes: A systematic literature review.

BACKGROUND AND OBJECTIVES: Despite the growing body of evidence characterising the association between serum potassium levels and adverse clinical outcomes, a contemporary summary of available evidence is currently lacking. The objective of this study, therefore, was to undertake a systematic literature review to identify all relevant evidence assessing risk factors associated with the incidence of hyperkalaemia (HK) and also quantifying the effect of serum potassium levels on risk of adverse clinical outcomes. METHODS: PubMed (Medline and Medline In-Process), Embase and the Cochrane Library were searched for studies published between January 2002 and November 2018. Search inclusion criteria included studies describing either the incidence of HK events and any associated risk factors, or associations between HK or serum potassium concentration and adverse clinical outcomes including mortality, hospitalisation, major adverse cardiac events (MACE) and renin-angiotensin-aldosterone system inhibitors (RAASi) discontinuation in adult patients with chronic kidney disease (CKD), heart failure (HF), type 2 diabetes (T2DM) or hypertension. RESULTS: The search identified 1,897 publications. From these, a total of 123 studies met the inclusion criteria and were included in the review. The most commonly identified risk factors associated with HK events were the presence of CKD or renal impairment, T2DM, HF, hypertension, RAASi use and mineralocorticoid receptor antagonist use. Potassium levels both above and below the normal range were consistently associated with adverse clinical outcomes, with relative and absolute risks of outcomes increasing with severity of hyper- or hypokalaemia. These associations were consistently reported across a broad range of patient population types and study types. CONCLUSION: The current body of published evidence is compelling in its confirmation of the associations between serum potassium levels and adverse clinical outcomes. This review further highlights the importance of avoiding both hyper- and hypokalaemia, in order to reduce risk of mortality, hospitalisation, MACE and RAASi discontinuation or down-titration.

The value of maintaining normokalaemia and enabling RAASi therapy in chronic kidney disease.

BACKGROUND: People with chronic kidney disease (CKD) are at an increased risk of developing hyperkalaemia due to their declining kidney function. In addition, these patients are often required to reduce or discontinue guideline-recommended renin-angiotensin-aldosterone system inhibitor (RAASi) therapy due to increased risk of hyperkalaemia. This original research developed a model to quantify the health and economic benefits of maintaining normokalaemia and enabling optimal RAASi therapy in patients with CKD. METHODS: A patient-level simulation model was designed to fully characterise the natural history of CKD over a lifetime horizon, and predict the associations between serum potassium levels, RAASi use and long-term outcomes based on published literature. The clinical and economic benefits of maintaining sustained potassium levels and therefore avoiding RAASi discontinuation in CKD patients were demonstrated using illustrative, sensitivity and scenario analyses. RESULTS: Internal and external validation exercises confirmed the predictive capability of the model. Sustained potassium management and ongoing RAASi therapy were associated with longer life expectancy (+ 2.36 years), delayed onset of end stage renal disease (+ 5.4 years), quality-adjusted life-year gains (+ 1.02 QALYs), cost savings (£3135) and associated net monetary benefit (£23,446 at £20,000 per QALY gained) compared to an absence of RAASi to prevent hyperkalaemia. CONCLUSION: This model represents a novel approach to predicting the long-term benefits of maintaining normokalaemia and enabling optimal RAASi therapy in patients with CKD, irrespective of the strategy used to achieve this target, which may support decision making in healthcare.

Serum potassium as a predictor of adverse clinical outcomes in patients with chronic kidney disease: new risk equations using the UK clinical practice research datalink.

BACKGROUND: To address a current paucity of European data, this study developed equations to predict risks of mortality, major adverse cardiac events (MACE) and renin angiotensin-aldosterone system inhibitor (RAASi) discontinuation using time-varying serum potassium and other covariates, in a UK cohort of chronic kidney disease (CKD) patients. METHODS: This was a retrospective observational study of adult CKD patients listed on the Clinical Practice Research Datalink, with a first record of CKD (stage 3a-5, pre-dialysis) between 2006 and 2015. Patients with heart failure at index were excluded. Risk equations developed using Poisson Generalized Estimating Equations were utilised to estimate adjusted incident rate ratios (IRRs) between serum potassium and adverse outcomes, and identify other predictive clinical factors. RESULTS: Among 191,964 eligible CKD patients, 86,691 (45.16%), 30,629 (15.96%) and 9440 (4.92%) experienced at least one hyperkalaemia episode, when defined using serum potassium concentrations 5.0-< 5.5 mmol/L, 5.5-< 6.0 mmol/L and ≥ 6.0 mmol/L, respectively. Relative to the reference category (4.5 to < 5.0 mmol/L), adjusted IRRs for mortality and MACE exhibited U-shaped associations with serum potassium, with age being the most important predictor of both outcomes (P < 0.0001). A J-shaped association between serum potassium and RAASi discontinuation was observed; estimated glomerular filtration rate was most predictive of RAASi discontinuation (P < 0.0001). CONCLUSIONS: Hyperkalaemia was associated with increased mortality and RAASi discontinuation risk. These risk equations represent a valuable tool to predict clinical outcomes among CKD patients; and identify those likely to benefit from strategies that treat hyperkalaemia, prevent RAASi discontinuation, and effectively manage serum potassium levels.

Evidence in support of hyperkalaemia management strategies: A systematic literature review.

BACKGROUND: Hyperkalaemia is a potentially life-threatening condition that can be managed with pharmacological and non-pharmacological approaches. With the recent development of new hyperkalaemia treatments, new information on safe and effective management of hyperkalaemia has emerged. OBJECTIVES: This systematic literature review (SLR) aimed to identify all relevant comparative and non-comparative clinical data on management of hyperkalaemia in adults. Our secondary aim was to assess the feasibility of quantitatively comparing randomised controlled trial (RCT) data on the novel treatment sodium zirconium cyclosilicate (ZS) and established pharmacological treatments for the non-emergency management of hyperkalaemia, such as the cation-exchangers sodium/calcium polystyrene sulphonate (SPS/CPS). METHODS: MEDLINE, Embase and the Cochrane Library were searched on 3rd April 2017, with additional hand-searches of key congresses and previous SLRs. Articles were screened by two independent reviewers. Eligible records reported interventional or observational studies of pharmacological or non-pharmacological management of hyperkalaemia in adults. RESULTS: Database searches identified 2,073 unique records. Two hundred and one publications were included, reporting 30 RCTs, 29 interventional non-RCTs and 43 observational studies. Interventions investigated in RCTs included ZS (3), SPS/CPS (3), patiromer (4) and combinations of temporising agents (6 RCTs). A robust and meaningful indirect treatment comparison between ZS and long-established cation-binding agents (SPS/CPS) was infeasible because of heterogeneity between studies (including time points and dosing) and small sample size in SPS/CPS studies. CONCLUSIONS: Despite hyperkalaemia being associated with several chronic diseases, there is a paucity of high-quality randomised evidence on long-established treatment options (SPS and CPS) and a limited evidence base for hyperkalaemia management with these agents.

Understanding Patient Perspectives of the Impact of Anemia in Chronic Kidney Disease: A United States Patient Survey.

Anemia in chronic kidney disease (CKD) is associated with reduced health-related quality of life and physical functioning. This study investigated knowledge and awareness of anemia in patients with CKD in the United States (US) through an online, quantitative survey administered to patients aged ≥18 years with self-reported CKD, with or without anemia. Of 446 patients included, 255 (57.2%) were diagnosed with anemia and 191 (42.8%) were in the non-anemia cohort. In patients with anemia, 71.0% were aware of the relationship between CKD and anemia versus 52.9% in the non-anemia cohort. In the anemia cohort, 46.3% of patients were aware of their hemoglobin level, versus 27.2% in the non-anemia cohort. Despite 67.4% of patients with anemia believing their condition was well/very well managed, only 50% reported being informed about different treatments without prompting healthcare providers. In the US, patients with anemia and CKD perceived that anemia had a negative impact on physical health and emotional wellbeing. Results emphasize a lack of disease awareness, suggesting patients would benefit from further education on anemia in CKD.

Understanding Patient Perspectives and Awareness of the Impact and Treatment of Anemia with Chronic Kidney Disease: A Patient Survey in China.

BACKGROUND: Anemia is a common complication of chronic kidney disease (CKD) that may reduce patients' health-related quality of life (HRQoL). This study explored the experience and knowledge of patients with CKD, with and without anemia, in China. METHODS: A quantitative online survey was administered to 500 consenting Chinese patient volunteers aged ≥18 years with self-reported CKD, with or without anemia, between August 29, and September 17, 2018. Patients with cancer were excluded. The 27-question survey explored knowledge of anemia, HRQoL, anemia management, and interactions with healthcare providers. RESULTS: Of 456 evaluable patients, 148 (32.5%) reported having anemia and 262 (57.5%) did not. Knowledge of anemia and its symptoms varied, and approximately half of all patients did not know their hemoglobin level. Patients with anemia expressed an adverse impact of anemia on HRQoL, most commonly lack of energy (65.5%), sadness/depression (54.1%), and feeling ill (50.0%). The most frequently reported treatments among these patients were dietary advice (68.9%), iron supplements (63.5%), and oral medications (53.4%). Although 89.2% of patients with anemia trusted their healthcare providers above other information sources, only 29.0% reported seeking information from them; this was despite 92.6% reporting wanting further information and support about managing conditions like anemia. CONCLUSION: Our findings suggest that patients with CKD, both with and without anemia, would benefit from increased awareness of anemia and more in-depth discussions with healthcare providers in order to facilitate better management of CKD and optimization of treatment plans.

The Impact of CKD Anaemia on Patients: Incidence, Risk Factors, and Clinical Outcomes-A Systematic Literature Review.

Anaemia is a common consequence of chronic kidney disease (CKD); however, the risk factors for its development and its impact on outcomes have not been well synthesised. Therefore, we undertook a systematic review to fully characterise the risk factors associated with the presence of anaemia in patients with CKD and a contemporary synthesis of the risks of adverse outcomes in patients with CKD and anaemia. We searched MEDLINE, EMBASE, and the Cochrane Library from 2002 until 2018 for studies reporting the incidence or prevalence of anaemia and associated risk factors and/or associations between haemoglobin (Hb) or anaemia and mortality, major adverse cardiac events (MACE), hospitalisation, or CKD progression in adult patients with CKD. Extracted data were summarised as risk factors related to the incidence or prevalence of anaemia or the risk (hazard ratio (HR)) of outcome by Hb level (<10, 10-12, >12 g/dL) in patients not on dialysis and in those receiving dialysis. 191 studies met the predefined inclusion criteria. The risk factor most associated with the prevalence of anaemia was CKD stage, followed by age and sex. Mean HRs (95% CI) for all-cause mortality in patients with CKD on dialysis with Hb <10, 10-12, and >12 g/dL were 1.56 (1.43-1.71), 1.17 (1.09-1.26), and 0.91 (0.87-0.96), respectively. Similar patterns were observed for nondialysis patients and for the risks of hospitalisation, MACE, and CKD progression. This is the first known systematic review to quantify the risk of adverse clinical outcomes based on Hb level in patients with CKD. Anaemia was consistently associated with greater mortality, hospitalisation, MACE, and CKD progression in patients with CKD, and risk increased with anaemia severity. Effective treatments that not only treat the anaemia but also reduce the risk of adverse clinical outcomes are essential to help reduce the burden of anaemia and its management in CKD.

Drug treatment patterns and work productivity in chronic kidney disease patients with anemia in China: Cross sectional analysis of real-world data.

BACKGROUND: We explored the association of anemia severity in patients with chronic kidney disease (CKD) and anemia treatment with work productivity in China. METHODS: Cross-sectional survey data from Chinese physicians and their CKD patients were collected in 2015. Physicians recorded demographics, disease characteristics, and treatment. Patients completed the Work Productivity and Activity Impairment questionnaire. Data were stratified by dialysis-dependence, hemoglobin (Hb) level, and anemia treatment. RESULTS: Based on data from 1,052 patients (704 non-dialysis-dependent [NDD] and 348 dialysis-dependent [DD] patients), prescribed anemia treatment differed significantly across Hb levels (P < 0.001). In NDD patients, anemia treatment also differed significantly by on-treatment Hb level (P < 0.001). In treated NDD patients with Hb < 10 g/ dL, Hb 10 to 12 g/dL, and Hb > 12 g/dL, 31%, 59%, and 38% of patients, respectively, were prescribed oral iron, and 34%, 19%, and 0% of patients, respectively, were prescribed oral iron with erythropoiesis-stimulating agents (ESA). NDD patients were less likely to be prescribed any anemia treatment, and ESA specifically, than DD patients. When treated, 67% and 45% of NDD and DD patients, respectively, had Hb ≥ 10 g/dL (P < 0.001). Overall work and activity impairment differed significantly across Hb levels in NDD and DD patients, with the least impairment observed at the highest Hb level. CONCLUSION: Approximately 40% of NDD patients and 60% of DD patients receiving anemia treatment had Hb < 10 g/dL. Compared with mild anemia patients, severe anemia patients were more likely to be treated for anemia and have impaired work productivity. Chinese CKD patients could benefit from improved anemia treatment.

Predictors for repeated hyperkalemia and potassium trajectories in high-risk patients - A population-based cohort study.

Understanding predictors and trajectories of increased potassium may inform testing and treatment of hyperkalemia. We examined predictors for repeated hyperkalemia among patients after first-time renin angiotensin system inhibitor (RASi) prescription, chronic kidney disease (CKD), or chronic heart failure (CHF); and we also examined potassium trajectories in these patients after their first hyperkalemia event. We used Danish population-based registries to identify all patients with first-time RASi prescription, incident CKD, or incident CHF (2000-2012). For patients with a first hyperkalemia event, potassium trajectories over the following 6 months were examined. The predictors associated with repeated hyperkalemia were assessed, with repeated hyperkalemia defined as a potassium test >5.0 mmol/L after the first event within 6 months. Overall 262,375 first-time RASi users, 157,283 incident CKD patients, and 14,600 incident CHF patients were included. Of patients with a first hyperkalemia event, repeated hyperkalemia within 6 months occurred in 37% of RASi users, 40% with CKD, and 49% of patients with CHF. Predictors included severe hyperkalemia, low eGFR, diabetes, and spironolactone use. In all cohorts, the median potassium levels declined over 2-4 weeks after a hyperkalemia event for the first time, but reverted to levels higher than before the initial hyperkalemia event in those who had repeated hyperkalemia. Following hyperkalemia, discontinuation of RASi and spironolactone was common in the RASi and CHF cohorts. Repeated hyperkalemia was common among the explored cohorts. The first hyperkalemia event was an indicator of increased median potassium levels. Predictors may identify patients likely to benefit from intensified monitoring and intervention.

Healthcare resource utilisation and cost associated with elevated potassium levels: a Danish population-based cohort study.

OBJECTIVES: To investigate healthcare costs associated with hyperkalaemia (HK) among patients with chronic kidney disease (CKD), heart failure (HF) or diabetes. DESIGN: Before-after cohort study of patients with HK and matched patients without HK. SETTING: Population-based databases covering primary and secondary care for the entire of Northern Denmark. PARTICIPANTS: Patients with a first incident record of CKD (n=78 372), HF (n=14 233) or diabetes (n=37 479) during 2005-2011. Among all patients experiencing a first HK event (potassium level >5.0 mmol/L), healthcare costs were compared during 6 months before and 6 months after the HK event. The same cost assessment was conducted 6 months before and after a matched index date in a comparison cohort of patients without HK. PRIMARY AND SECONDARY OUTCOME MEASURES: Mean costs of hospital care, general practice and dispensed drugs converted to 2018 Euros. RESULTS: Overall, 17 747 (23%) CKD patients, 5141 (36%) HF patients and 4183 (11%) diabetes patients with a first HK event were identified. More than 40% of all HK patients across the patient groups had subsequent HK events with successively shorter times between the events. In CKD patients, overall mean costs were €5518 higher 6 months after versus before first HK, while €441 higher in matched CKD patients without HK, yielding HK-associated costs of €5077. Corresponding costs associated with a HK event were €6018 in HF patients, and €4862 in diabetes patients. CONCLUSIONS: Among CKD, HF and diabetes patients, an incident HK event was common, and a large proportion of the patients experienced recurrent HK events. Substantial increase in healthcare costs associated with a HK event was observed in the HK patients compared with non-HK patients. These results are important to better understand the potential economic impact of HK among high-risk comorbid patients in a real-wold setting and help inform decision-making for clinicians and healthcare providers.

Serum potassium and clinical outcomes in heart failure patients: results of risk calculations in 21 334 patients in the UK.

AIMS: At present, the clinical burden of hypokalaemia and hyperkalaemia among European heart failure patients, and relationships between serum potassium and adverse clinical outcomes in this population, is not well characterized. The aim of this study was to investigate associations between mortality, major adverse cardiac events, and renin-angiotensin-aldosterone system inhibitor (RAASi) discontinuation across serum potassium levels, in a UK cohort of incident heart failure patients. METHODS AND RESULTS: This was a retrospective observational cohort study of newly diagnosed heart failure patients listed in the Clinical Practice Research Datalink, with a first record of heart failure (index date) between 2006 and 2015. Hypokalaemia and hyperkalaemia episodes were defined as the number of serum potassium measurements exceeding each threshold (<3.5, ≥5.0, ≥5.5, and ≥6.0 mmol/L), without such a measurement in the preceding 7 days. Risk equations developed using Poisson generalized estimating equations were utilized to estimate adjusted incident rate ratios (IRRs) relating serum potassium and clinical outcomes (death, major adverse cardiac event, and RAASi discontinuation). Among 21,334 eligible heart failure patients, 1969 (9.2%), 7648 (35.9%), 2725 (12.8%), and 763 (3.6%) experienced episodes of serum potassium <3.5, ≥5.0, ≥5.5, and ≥6.0 mmol/L, respectively. The adjusted IRRs for mortality exhibited a U-shaped association pattern with serum potassium. Relative to the reference category (4.5 to <5.0 mmol/L), adjusted IRRs for mortality were estimated as 1.98 (95% confidence interval: 1.69-2.33), 1.23 (1.12-1.36), 1.35 (1.14-1.60), and 3.02 (2.28-4.02), for patients with serum potassium <3.5, ≥5.0 to <5.5, ≥5.5 to <6.0, and ≥6.0 mmol/L, respectively. The adjusted IRRs for major adverse cardiac events demonstrated a non-statistically significant relationship with serum potassium. Discontinuation of RAASi therapy exhibited a J-shaped trend in association with serum potassium. Compared with the reference category (4.5 to <5.0 mmol/L), adjusted IRRs were estimated as 1.07 (0.89-1.28) in patients with serum potassium <3.5 mmol/L, increasing to 1.32 (1.14-1.53) and 2.19 (1.63-2.95) among those with serum potassium ≥5.5 to <6.0 and ≥6.0 mmol/L, respectively. CONCLUSIONS: In UK patients with new onset heart failure, both hypokalaemia and hyperkalaemia were associated with increased mortality risk, and hyperkalaemia was associated with increased likelihood of RAASi discontinuation. Our results demonstrate the potential importance of serum potassium monitoring for heart failure outcomes and management.

Development of a health economic model to evaluate the potential benefits of optimal serum potassium management in patients with heart failure.

AIMS: Patients with heart failure are at increased risk of hyperkalemia, particularly when treated with renin-angiotensin-aldosterone system inhibitor (RAASi) agents. This study developed a model to quantify the potential health and economic value associated with sustained potassium management and optimal RAASi therapy in heart failure patients. MATERIALS AND METHODS: A patient-level, fixed-time increment stochastic simulation model was designed to characterize the progression of heart failure through New York Heart Association functional classes, and predict associations between serum potassium levels, RAASi use, and consequent long-term outcomes. Following internal and external validation exercises, model analyses sought to quantify the health and economic benefits of optimizing both serum potassium levels and RAASi therapy in heart failure patients. Analyses were conducted using a UK payer perspective, independent of costs and utilities related to pharmacological potassium management. RESULTS: Validation against multiple datasets demonstrated the predictive capability of the model. Compared to those who discontinued RAASi to manage serum potassium, patients with normokalemia and ongoing RAASi therapy benefited from longer life expectancy (+1.38 years), per-patient quality-adjusted life year gains (+0.53 QALYs), cost savings (£110), and associated net monetary benefit (£10,679 at £20,000 per QALY gained) over a lifetime horizon. The predicted value of sustained potassium management and ongoing RAASi treatment was largely driven by reduced mortality and hospitalization risks associated with optimal RAASi therapy. LIMITATIONS: Several modeling assumptions were made to account for a current paucity of published literature; however, ongoing refinement and validation of the model will ensure its continued accuracy as the clinical landscape of hyperkalemia evolves. CONCLUSIONS: Predictions generated by this novel modeling approach highlight the value of sustained potassium management to avoid hyperkalemia, enable RAASi therapy, and improve long-term health economic outcomes in patients with heart failure.

A Matching-Adjusted Indirect Comparison of Sonidegib and Vismodegib in Advanced Basal Cell Carcinoma.

OBJECTIVES: Based on single-arm trial data (BOLT), sonidegib was approved in the US and EU to treat locally advanced basal cell carcinomas (BCCs) ineligible for curative surgery or radiotherapy. Vismodegib, the other approved targeted therapy, also was assessed in a single-arm trial (ERIVANCE). We examined the comparative effectiveness of the two drugs using a matching-adjusted indirect comparison (MAIC) versus an unadjusted indirect comparison. METHODS: After comparing trials and identifying potential prognostic factors, an MAIC was conducted to adjust for differences in key patient baseline characteristics. Due to BOLT's small sample size, the number of matching variables was restricted to two. Efficacy results for sonidegib were generated so that selected baseline characteristics matched those from ERIVANCE and were compared with published ERIVANCE results. RESULTS: Matching variables were baseline percentages of patients receiving prior radiotherapy and surgery. After weighting, sonidegib objective response rate (ORR) and median progression-free survival (PFS) were effectively unchanged (prematched versus postmatched ORR and PFS, 56.1% versus 56.7% and 22.1 versus 22.1 months, resp.). Vismodegib's ORR and PFS were 47.6% and 9.5 months. CONCLUSIONS: Comparative effectiveness of sonidegib versus vismodegib remains unchanged after adjusting BOLT patient-level data to match published ERIVANCE baseline percentages of patients receiving prior surgery and radiotherapy.